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Page 4 Brault et al. J Transl Genet Genom. 2025;9:1-10 https://dx.doi.org/10.20517/jtgg.2024.83

[63]
found on the inner mitochondrial membrane tightly bound to cardiolipin . NME4 catalyzes the phospho-
transfer between guanines and adenines (ATP + GDP ↔ ADP + GTP). CK is abundant within mitochondria
[64]
and the cytosol, and functions as a spatial and temporal buffer of ATP . The octameric mitochondrial
[65]
isoform of CK binds tightly to cardiolipin . CK catalyzes the phospho-transfer of ATP to creatine (ATP +
Cr ↔ ADP + PCr). Both NME4 and CK may also transfer cardiolipin between the inner and outer
mitochondrial membranes, particularly when affecting apoptosis [66,67] .

ENERGETIC STATE OF BARTH SYNDROME
Note
References chosen for this section were initially identified in PubMed or Scopus with a search for Tafazzin
and ATP. We selected all those studies that performed measures of ATP in cells/tissues with mutated
Tafazzin or decreased Tafazzin protein amounts.

Cell studies
Numerous groups have measured ATP and/or ADP in cell culture models of cardiolipin insufficiency,
mimicking the BTHS condition. Significantly, using immortalized lymphoblasts from BTHS patients, ATP,
ADP, and AMP levels were all increased, which is thought to result from a compensatory increase in
mitochondrial content . Likewise, ATP is increased when wild-type TAFAZZIN is knocked down in
[68]
cultured cardiomyocytes or knocked out in mouse embryonic fibroblasts . In contrast, ATP levels are
[53]
[70]
[44]
[69]
decreased in fibroblasts , lymphocytes , and inducible pluripotent stem cell-derived cardiomyocytes
from BTHS patients. Further, ATP is also decreased with shRNA knock-down of Tafazzin in rat neonatal
[50]
ventricular myocytes [60,71,72] and in HeLA cells , as illustrated in Table 1. Because loss of cardiolipin has clear
inhibitory effects on mitochondrial ATP production, it may be surprising that ATP content is not
consistently lower across cell types. Potential explanations could be the different metabolic substrates (often
very high glucose in vitro), very low energy demand, lack of cross-talk between cell types, and the ability of
many cells to vary ATP production between glycolysis and OxPhos. Indeed, since ATP is necessary for cell
survival, it must be true that the steady-state ATP production rate must match the ATP use rate. Thus,
although ATP is often used as a surrogate marker for mitochondrial dysfunction in BTHS, care should be
exercised as there may be many ways that energetics can be disassociated.

Mouse models: In mouse models, it remains unclear whether the doxycycline-inducible Tafazzin knock-
down (Taz ) or knock-out (Taz ) mice mutant models exhibit ATP content anomalies, but ATP synthesis
KD
KO
(mitochondrial F0F1-ATP synthase) and ADP-ATP carrier abundance are both decreased [76,77] . In a patient-
tailored point mutant knock-in (Taz D75H ) mouse model of BTHS that expresses a stable mutant protein, ATP
is lower in the adult heart tissue, with no change in ADP or AMP levels; therefore, the ADP/ATP ratio is
higher in adult point-mutant knock-ins. However, no differences were seen in juveniles, demonstrating that
the energetic state becomes unstable with disease progression . Moreover, despite Taz D75H mutants
[42]
[78]
exhibiting total infertility, there was no decrease in ATP, ADP or AMP in mutant testis , suggesting that
not all knock-in mutant organs are equally energetically challenged. In a different model of cardiolipin
deficiency, knock-out of 3-hydroxyacyl-coenzyme A dehydratase (HACD), ATP content was much lower
after an exercise bout in the HACD knock-outs versus the wild-type controls , suggesting that
[45]
mitochondrial generation was relatively slowed. Similarly, when CL biosynthesis was interrupted via
targeted mitochondrial PTPMT1 phosphatase deletion in hearts, ATP synthesis was impaired, resulting in
[79]
abnormal heart development and neonatal lethality . However, no direct measures of the non-contracted
skeletal muscle energetic state (e.g., ATP and ADP) have been reported in any of the mouse models of
BTHS.